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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Regarding tissue selectivity, whereas tamoxifen has a beneficial side effect due to its agonist actions on preserving bone mineral density and protection of the cardiovascular system by reducing plasma lipids, its agonist effect on the gynecological tract presents a small but significant risk of initiating endometrial cancer. This is thought to be due to an inability to block activation of AF1, which represents a significant mechanistic pathway in the uterus. In support of this, pure antiestrogens such as fulvestrant (FaslodexTM) prevent activation of both AF1 and AF2 and thus have only antagonist effects.
Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
A understanding of xenobiotic biotransformation is one of science’s most notable examples of the practical applications and societal benefits derived from basic research. Studies on xenobiotic biotransformation have defined the roles of genetics, age, diet, and various environmental factors, and have demonstrated the importance of induction and inhibition in xenobiotic/drug exposures in individual sensitivity to chemicals [see Conney (1982) for numerous examples]. Perhaps the most important concept derived from research on xenobiotic biotransformation is that electrophiles generated during the process initiate toxicity and carcinogenicity by binding to critical cellular nucleophiles (Miller and Miller, 1981b). This concept has been the driving force behind a significant portion of research in carcinogenesis, toxicology, and pharmacology and has been utilized to assess the toxic and carcinogenic potential of drugs and xenobiotics [see Hammons et al. (1985) for an example] and to design chemotherapeutic regimens with enhanced tissue selectivity and drug analogs with reduced toxicity. Studies on the mechanisms of genetic control of the Ah locus (Nebert and Gonzalez, 1987) have contributed to current concepts on genetic regulation of enzyme and cellular function and to understanding the genetic basis for adaptive responses that provide cells’ selective survival advantage in response to environmental insult.
Sympathomimetic Amines: Actions and Uses
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Prenalterol (H 133/80, (−)isomer) was introduced as a cardioselective β1-adrenoceptor partial agonist which displayed selective inotropic activity. Its selectivity is not now attributed to preferential binding at β1-adrenoceptors but to a greater efficacy; it displays tissue selectivity (Chapter 3, Kenakin & Beek 1982a). It does not produce a fall in arterial blood pressure, probably because of the lack of efficacy at vascular β2-adrenoceptors. This may be an advantage in not inducing reflex tachycardia, but a possible disadvantage is that it does not reduce after-load on the heart. The reduced tachycardia may be due to either reflex cardiac slowing because of modest increases in blood pressure or to β-adrenoceptor blockade when there is high sympathetic drive (Kenakin & Beek 1982b). Prenalterol was introduced for clinical use in the UK but has since been withdrawn. In isolated cardiac tissue from heart failure patients its inotropic activity is weak.
Evaluating gliclazide for the treatment of type 2 diabetes mellitus
Published in Expert Opinion on Pharmacotherapy, 2022
Brian Tomlinson, Yan-Hong Li, Paul Chan
Like other sulfonylureas, gliclazide binds to the sulfonylurea receptor (SUR) and inhibits potassium efflux through ATP-sensitive potassium (KATP) channels, resulting in the opening of voltage-gated calcium channels and the influx of calcium that causes the release of insulin from the pancreatic beta-cells. The KATP channels comprise four inwardly-rectifying potassium (Kir) channel subunits and the sulfonylureas and glinides can bind to the SUR and the Kir subunits at two binding sites [21]. The second-generation sulfonylureas with the N-containing heterocyclic ring bind to both sites, whereas gliclazide and the first-generation sulfonylureas only bind to one site (Figure 1). Whether this receptor binding influences tissue selectivity is not certain [24]. Apart from the beta-cells of the pancreas, KATP channels are present in other cells, including cardiac myocytes, vascular smooth muscle, skeletal muscle and neurons, and sulfonylureas may have harmful effects by binding to KATP channels in those tissues [25].
Towards precision nanomedicine for cerebrovascular diseases with emphasis on Cerebral Cavernous Malformation (CCM)
Published in Expert Opinion on Drug Delivery, 2021
Andrea Perrelli, Parisa Fatehbasharzad, Valerio Benedetti, Chiara Ferraris, Marco Fontanella, Elisa De Luca, Mauro Moglianetti, Luigi Battaglia, Saverio Francesco Retta
The extensively growing field of nanomedicine offers excellent solutions for site-specific targeting, biological imaging, controlled drug delivery and release, and efficient therapy for a wide range of CNS diseases, including cerebrovascular, neurological, and neoplastic [109–117]. Compared with conventional medicines, nanomedicines have many physical and biological advantages, such as improved solubility and pharmacokinetics, enhanced efficacy, reduced toxic side effects, and increased tissue selectivity, thus overcoming the major shortcomings of conventional therapeutic approaches [118]. In recent years, multiple nanosystems have indeed been developed for advanced therapeutic and diagnostic applications, including controlled targeting of nanoengineered therapeutic agents to pathological sites (nanotherapeutics) and visualization/quantitation of pathophysiological processes (nanodiagnostics), as well as for combinatorial approaches (nanotheranostics). In particular, the latter combines diagnostic and therapeutic properties within the same nanocarrier, thus providing innovative and effective solutions for advanced personalized nanomedicine interventions, including the possibility of simultaneous imaging, monitoring, and therapy [113,119,120]. Furthermore, the emerging integration of nanotechnology with stem cell therapy and tissue engineering is providing novel promising options for treatment of brain and spinal cord injury associated with cerebrovascular diseases [91,121].
Stimuli-responsive drug delivery systems for head and neck cancer therapy
Published in Drug Delivery, 2021
Jingou Liang, Bina Yang, Xuedong Zhou, Qi Han, Jing Zou, Lei Cheng
Head and neck cancer (HNC) refers to epithelial malignancies of the paranasal sinuses, nasal cavity, oral cavity, pharynx, and larynx. The high incidence and prevalence of HNC profoundly influence human health and reduce the quality of life (Mehanna et al., 2011). In the 2017 global burden of disease study, around 678,900 incident cases were reported. According to the report from GLOBOCAN, around 450,000 estimated new cases of oral cavity and pharyngeal cancer and 23,000 estimated deaths were reported worldwide in 2018 (Fitzmaurice, 2018). Squamous cell carcinoma (SCC) is the most frequently diagnosed HNC. Previous researches have shown that the risk factors of HNC include tobacco intake, heavy alcohol consumption, human papillomavirus (HPV), betel quid, and additional factors such as certain microorganisms and environmental pollutants (Marur & Forastiere, 2016). The current management of HNC is stage-dependent and based on the multidisciplinary teamwork. Especially, Stage III or IV HNCs need the combination of surgical treatment and other forms of adjuvant treatment such as chemotherapy, phototherapy, hyperthermia, gene therapy, etc. (Feller & Lemmer, 2012; Chi et al., 2015). However, there are still some problems remains unsolved, including low tissue selectivity, poor drug solubility, unfavorable bioavailability, chemical instability and systemic adverse side effects of traditional drug administration (Koo et al., 2005; Godin et al., 2011; Epstein et al., 2012; Gong et al., 2012). Besides, drug resistance and cancer recurrence have become great challenges during the clinical application. Even worse, multidrug resistance (MDR) has been reported in many cases of HNC, which leads to the recurrence and progression of HNC (Pérez-Sayáns et al., 2010).